Calcific aortic valve stenosis (CAVS) is the most common indication for surgical valve replacement in the United States, requiring valvuloplasty or surgical replacement. CAVS has been thought for years as a passive degenerative process, but accumulating data from recent studies of human patients have shifted the paradigm by suggesting that it is a complex syndrome involving multiple active cellular processes. The current hypothesis is that disruption of the endothelial barrier of aortic valvular leaflets is the early pathological event triggering a cascade of inflammation and degenerative processes leading to calcific valves. New animal models of CAVS, however, are needed to test this hypothesis. Moreover, better understanding of molecular mechanisms of valvular endothelial damage and its consequence may provide a potential target for novel non- invasive therapies that prevents disease progression. Here, we propose to build a new mouse model that not only can fully recapture the pathology of human CAVS but also allow us to address mechanistically the early valvular endothelial injury and subsequent inflammation and degenerative processes. This mouse CAVS model will be generated by genetically disrupt EGFR gene in the valvular endothelium using a novel valvular endothelial specific Cre mouse line and a conditional floxed EGFR mouse line. We will characterize the pathology of CAVS and identify molecular alterations responsible for endothelial injury, inflammation, and degeneration using transcriptional profiling and RNA interference. At the conclusion of this study, we will have generated and characterized a novel mouse model of CAVS for further studying the pathogenesis of CAVS and identifying for drug targets for this common devastating human disease. PUBLIC HEALTH RELEVANCE: The goal of this project is to build a new mouse model of calcific aortic valve stenosis to study the underlying pathogenesis. Completion of this project will help to develop new therapeutic and preventive strategies for this devastating human disease.